The program of work described in this supplemental application translates the conceptual frameworks developed under our-present grant into computer programs that enable us to predict behavior, quantitate parameters and reveal contradictions in our interpretation of the data on immune system function. [unreadable] The role of evolution of infectious diseases (of the order of hours) is vastly more rapid than the rate of evolution of vertebrate hosts which evolve at a rate of the order of years. The crafty solution of natural selection was a biodestructive protective mechanism that could somatically evolve on a time scale close to that of bacteria and viruses. In order to achieve this rapid rate of evolution, the immune system must somatically sort its large and random repertoire into anti-Self (to be inactivated) and anti-nonself (to be activated). Discovering how this is achieved is one of the major specific aims of this program of work. Other regulatory events control the class and magnitude of the antibody response. Collectively, these are principal area of investigation. [unreadable] This particular program of work is designed to tackle the larger integrative issues of immune regulation. A huge effort goes into working out details of mechanism, but much less effort is directed at finding the balance between the competing demands of the organism and its protective mechanisms. One reason for this neglect is the sheer magnitude of the problem. However, this can be ameliorated by the judicious use of computer stimulation tools that are able to absorb the data and keep track of the many selection pressures that govern the final state of the immune response to a given infectious disease. [unreadable] The proposed program of work depends on the results from many different experimental test systems. A unique feature of this proposal is to make the computer freely available to all members of the immunological community via the internet and the ubiquitous web browser installed on every computer. These programs will be of value not only to immunologists, but also to evolutionary biologists and clinicians interested in the origins of immunopathology [unreadable] [unreadable]